Atherosclerosis is the leading cause of morbidity and mortality worldwide. The situation will worsen due to the current epidemic of diabetes, obesity and metabolic syndrome if there is no improvement in its management. Statin trials have provided the major evidence for the benefits of an LDL-c lowering therapy and statin therapy is now the mainstay of cardiovascular disease clinical management. However, there are many instances of unresponsiveness and intolerance. There is thus an urgent need for additional approaches to lower plasma LDL-c, preferably acting synergistically with statins. Blocking very low density lipoprotein (VLDL) secretion has long been recognized as one of the alternatives. However, it can have unwanted consequences, because VLDL secretion is a hepatic-specific defense to protect against the excessive liver triglyceride accumulation seen in nutritional overload or metabolic syndrome. Thus targeting VLDL secretion without causing hepatic lipid accumulation is challenging. Phospholipid transfer protein (PLTP) is a potential therapeutic target for lowering plasma LDL-c levels in humans. Our early work indicates that it is the lack of hepatic PLTP, by decreasing VLDL secretion that is responsible for the reduced LDL-c levels in PLTP deficient mice. Perhaps most significantly, in mice on either a chow or high fat diet, global PLTP inhibition did not cause hepatic lipid accumulation. The major goal of this proposal is to develop an approach for the reduction of hepatic PLTP function and hence plasma LDL-c without causing hepatic lipid accumulation. We reasoned that identifying pathways and proteins associated with PLTP had the potential to reveal additional avenues for regulation of hepatic PLTP function. Based on preliminary work, we propose to characterize the interaction between furin, a member of the proprotein convertase family, and PLTP in vivo, and determine its effect on plasma lipid levels. In particular, we will investigate the underlying mechanisms by which overexpression of profurin (the N-terminal fragment of the full-length furin) reduces the effects o PLTP in promoting VLDL secretion. Furthermore, the therapeutic potential of a profurin-based strategy for the lowering of plasma LDL-c levels will be evaluated in mice. We anticipate that this project will broaden our understanding of both PLTP and furin biology and provide evidence for a novel strategy for lowering plasma LDL-c levels that will be effective in humans.